U.S. patent number 5,130,330 [Application Number 07/473,008] was granted by the patent office on 1992-07-14 for nitrogen-containing cyclohetero cycloalkylaminoaryl derivatives for cns disorders.
This patent grant is currently assigned to G. D. Searle & Co.. Invention is credited to Wayne D. Bowen, Patricia C. Contreras, Brian R. de Costa, Nancy M. Gray, Arthur E. Jacobson, Lilian A. Radesca, Kenner C. Rice, Andrew Thurkauf.
United States Patent |
5,130,330 |
de Costa , et al. |
July 14, 1992 |
Nitrogen-containing cyclohetero cycloalkylaminoaryl derivatives for
CNS disorders
Abstract
Certain nitrogen-containing cyclohetero cycloalkylaminoaryl
compounds are described for treatment of CNS disorders such as
cerebral ischemia, psychotic disorders and convulsions. Compounds
of particular interest are of the formula ##STR1## wherein R.sup.1
is selected from hydrido, loweralkyl, cycloalkylalkyl of four to
six carbon atoms, and loweralkenylloweralkyl; wherein each of
R.sup.2 and R.sup.3 is independently selected from hydrido and
loweralkyl; wherein each of R.sup.4 through R.sup.7, R.sup.10 and
R.sup.11 is independently selected from hydrido, hydroxy,
loweralkyl, benzyl, phenoxy, benzyloxy and haloloweralkyl; wherein
n is a number selected from four through six; wherein p is a number
selected from zero through four; wherein q is a number selected
from three through five; wherein A is selected from phenyl,
naphthyl and thienyl; wherein any of the foregoing A groups can be
further substituted with one or more substituents independently
selected from hydrido, hydroxy, loweralkyl, loweralkoxy, halo,
haloloweralkyl, amino, monoloweralkylamino and diloweralkylamino;
or a pharmaceutically acceptable salt thereof.
Inventors: |
de Costa; Brian R.
(Gaithersburg, MD), Rice; Kenner C. (Bethesda, MD), Gray;
Nancy M. (Ellisville, MO), Contreras; Patricia C.
(Ballwin, MO), Jacobson; Arthur E. (Potomac, MD),
Thurkauf; Andrew (Branford, CT), Radesca; Lilian A.
(Brookeville, MD), Bowen; Wayne D. (East Providence,
RI) |
Assignee: |
G. D. Searle & Co.
(Chicago, IL)
|
Family
ID: |
23877800 |
Appl.
No.: |
07/473,008 |
Filed: |
January 31, 1990 |
Current U.S.
Class: |
514/429;
548/578 |
Current CPC
Class: |
A61P
25/00 (20180101); C07D 295/135 (20130101) |
Current International
Class: |
C07D
295/135 (20060101); C07D 295/00 (20060101); A61K
031/40 (); C07D 295/073 () |
Field of
Search: |
;558/578 ;514/429 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
4204003 |
May 1980 |
Szmuszkovicz |
4460600 |
July 1984 |
Kaplan et al. |
4463013 |
July 1984 |
Collins et al. |
4466977 |
August 1984 |
McMillan et al. |
4801604 |
January 1989 |
Von Voigtlander et al. |
4855316 |
August 1989 |
Horwell et al. |
4876269 |
October 1989 |
Pennev et al. |
4891382 |
January 1990 |
Lancaster et al. |
|
Other References
S M. Rothman and J. W. Olney, "Glutamate and the Pathophysiology of
Hypoxia--Ischemic Brain Damage," Annals of Neurology, vol. 19, No.
2 (1986). .
C. Carter et al, J. Pharm. Exp. Ther., 247, (3), 1222-1232 (1988).
.
A. F. Gilman et al, The Pharmacological Basis of Therapeutics, 7th
Edn., p. 404, MacMillan (1985). .
C. G. Parsons et al, Neuropharm., 25(2), 217-220 (1986). .
W. Lason et al, Brain Res., 482, 333-339 (1989). .
B. R. de Costa et al, J. Med. Chem., 32(8), 1996-2002
(1989)..
|
Primary Examiner: Brust; Joseph Paul
Attorney, Agent or Firm: Keane; J. Timothy Smith; Charles E.
Matukaitis; Paul D.
Claims
What is claimed is:
1. A compound selected from
(.+-.)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)cyclo
hexylamine;
1S,2S-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)
cyclohexylamine; and
1R,2S-(+)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)cy
clohexylamine;
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a
therapeuticallyeffective amount of an active compound for treating
or preventing a CNS-related disorder and a
pharmaceutically-acceptable carrier or diluent, said active
compound selected from a compound of claim 1.
3. A method for treating a patient afflicted with or susceptible to
a CNS-related disorder, which method comprises administering to the
patient a therapeutically-effective amount of a compound of claim
1.
Description
FIELD OF THE INVENTION
This invention is in the field of clinical neurology and relates
specifically to a class of therapeutically useful compounds,
compositions and methods for treatment of Central Nervous System
(CNS) dysfunctions, neurotoxic damage, or neurodegenerative
diseases. For example, these compounds are particularly useful for
treating neurotoxic injury which follows periods of hypoxia, anoxia
or ischemia associated with stroke, cardiac arrest or perinatal
asphyxia. These compounds are also useful as antipsychotics and
anticonvulsives.
BACKGROUND OF THE INVENTION
Unlike other tissues which can survive extended periods of hypoxia,
brain tissue is particularly sensitive to deprivation of oxygen or
energy. Permanent damage to neurons can occur during brief periods
of hypoxia, anoxia or ischemia. Neurotoxic injury is known to be
caused or accelerated by certain excitatory amino acids (EAA) found
naturally in the central nervous system (CNS). Glutamate (Glu) is
an endogenous amino acid which has been characterized as a fast
excitatory transmitter in the mammalian brain. Glutamate is also
known as a powerful neurotoxin capable of killing CNS neurons under
certain pathological conditions which accompany stroke and cardiac
arrest. Normal glutamate concentrations are maintained within brain
tissue by energy-consuming transport systems. Under low energy
conditions which occur during conditions of hypoglycemia, hypoxia
or ischemia, cells can release glutamate. Under such low energy
conditions the cell is not able to take glutamate back into the
cell. Initial glutamate release stimulates further release of
glutamate which results in an extracellular glutamate accumulation
and a cascade of neurotoxic injury.
It has been shown that the sensitivity of central neurons to
hypoxia and ischemia can be reduced by either blockage of synaptic
transmission or by the specific antagonism of postsynaptic
glutamate receptors [see S. M. Rothman and J. W. Olney, "Glutamate
and the Pathophysiology of Hypoxia - Ischemic Brain Damage," Annals
of Neurology, Vol. 19, No. 2 (1986)]. Glutamate is characterized as
a broad spectrum agonist having activity at three neuronal
excitatory amino acid receptor sites. These receptor sites are
named after the amino acids which selectively excite them, namely:
Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) and quisqualate
(QUIS).
Neurons which have EAA receptors on their dendritic or somal
surfaces undergo acute excitotoxic degeneration when these
receptors are excessively activated by glutamate. Thus, agents
which selectively block or antagonize the action of glutamate at
the EAA synaptic receptors of central neurons can prevent
neurotoxic injury associated with hypoxia, anoxia, or ischemia
caused by stroke, cardiac arrest or perinatal asphyxia.
It is known that compounds of various structures, such
aminophosphonovalerate derivatives and piperidine dicarboxylate
derivatives, may act as competitive antagonists at the NMDA
receptor. Certain piperidineethanol derivatives, such as ifenprodil
and 1-(4-chlorophenyl)-2-[1-(4-fluorophenyl) piperidinyl]ethanol,
which are known antiischemic agents, have been found to be
non-competitive NMDA receptor antagonists [C. Carter et al, J,
Pharm Exp. Ther., 247 (3), 1222-1232 (1988)].
There are many classes of compounds known for treatment of
psychotic disorders. For example, current therapeutic treatments
for psychoses use compounds classifiable as
phenothiazine-thioxanthenes, as phenylbutylpiperidines and also as
certain alkaloids. An example of a phenylbutylpiperidine compound
of current use in psychotic treatment therapy is haloperidol [A. F.
Gilman et al, The Pharmacological Basis of Therapeutics, 7th Edn.,
P. 404, MacMillan (1985)].
Certain nitrogen-containing cyclohetero cycloalkylaminoaryl
compounds are known for pharmaceutical purposes. For example, U.S.
Pat. No. 4,204,003 to Szmuszkovicz describes
N-(2-aminocyclopentyl)-N-alkanoylanilides as antidepressant
agents.
Certain aminocycloaliphatic benzamides have been described for
various uses. For example, U.S. Pat. No. 4,463,013 to Collins et al
describes aminocyclohexylbenzamides for use as diuretic agents. The
compound
(.+-.)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzene
acetamide has been evaluated for its selectivity as an amino acid
antagonist [C. G. Parsons et al, Neuropharm., 25 (2), 217-220
(1986)]. This same compound has been evaluated for its
neuroprotective activity against kainate-induced toxicity [W. Lason
et al, Brain Res., 482, 333-339 (1989)]. U.S. Pat. No. 4,801,604 to
Vonvoightlander et al describes certain
cis-N-(2aminocycloaliphatic)benzamides as anticonvulsants
including, specifically, the compound
cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzamide.
These benzeneacetamide derivatives, such as
trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetami
de, have been described as a highly selective ligand for kappa
opioid receptors. Such kappa opioid affinity is believed associated
with blockade of convulsions and protection from cerebral ischemia
[B. R. de Costa et al, J. Med. Chem., 32 (8), 1996-2002
(1989)].
Treatment of CNS disorders and diseases such as cerebral ischemia,
psychotic disorders and convulsions, as well as prevention of
neurotoxic damage and neurodegenerative diseases, may be
accomplished by administration of a therapeutically-effective
amount of a compound of the Formula I: ##STR2## wherein R.sup.1 is
selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenylalkyl,
alkynylalkyl, carboxyalkyl, alkanoyl, alkylsulfinyl, alkylsulfonyl,
arylsulfinyl and arylsulfonyl; wherein each of R.sup.2 and R.sup.3
is independently selected from hydrido, alkyl, cycloalkyl,
hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl,
aryl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, carboxyalkyl,
alkanoyl, alkoxycarbonyl, carboxy, cyanoalkyl, alkylsulfinyl,
alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein R.sup.2 and
R.sup.3 may be taken together to form a saturated or partially
unsaturated carbocyclic group having three to eight ring carbons;
wherein each of R.sup.4 through R.sup.11 is independently selected
from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl,
aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl,
hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy,
carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R.sup.4 and
R.sup.5 may be taken together to form oxo or to form a saturated or
partially unsaturated carbocyclic group having three to eight ring
carbons; wherein R.sup.6 and R.sup.7 may be taken together to form
oxo; wherein R.sup.8 and R.sup.9 may be taken together to form oxo;
wherein R.sup.10 and R.sup.11 may be taken together to form oxo;
wherein each of n and m is a number selected from one through four;
wherein each of p and q is a number selected from zero through
five; wherein each of X and Z is independently selected from
##STR3## wherein R.sup.12 may be selected from hydrido, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,
alkoxyalkyl, hydroxyalkyl, alkanoyl, aralkanoyl, aroyl, aminoalkyl,
monoalkylaminoalkyl and dialkylaminoalkyl; wherein each of R.sup.13
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy,
aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo,
cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl
and alkanoyl; wherein A is selected from aryl, heteroaryl, aryloxy,
heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino,
heteroarylamino, aralkylamino, heteroaralkylamino, arylthio,
heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of
the foregoing A groups can be further substituted with one or more
substituents independently selected from hydrido, hydroxy, alkyl,
cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy,
aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino,
monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl,
alkenyl and alkynyl; or a pharmaceutically-acceptable salt
thereof.
The family of compounds within Formula I is novel with the proviso
that each of the compounds embraced by Formula I is a cis isomer
with respect to the two nitrogen atoms of Formula I; or a
pharmaceutically acceptable salt thereof.
A preferred family of compounds of Formula I consists of those
compounds wherein R.sup.1 is selected from hydrido, alkyl,
cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl,
aralkyl, aryl, alkenylalkyl, alkynylalkyl and carboxyalkyl; wherein
each of R.sup.2 and R.sup.3 is independently selected from hydrido,
alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl,
alkoxyalkyl, aralkyl, aryl, alkenyl, alkynyl, alkenylalkyl,
alkynylalkyl, carboxyalkyl, alkanoyl, alkoxycarbonyl, carboxy and
cyanoalkyl; wherein R.sup.2 and R.sup.3 may be taken together to
form a saturated or partially unsaturated carbocyclic group having
three to eight ring carbons; wherein each of R.sup.4 through
R.sup.11 is independently selected from hydrido, hydroxy, alkyl,
cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy,
aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino,
monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl,
alkenyl and alkynyl; wherein R.sup.4 and R.sup.5 may be taken
together to form oxo or to form a saturated or partially
unsaturated carbocyclic group having three to eight ring carbons;
wherein each of n and m is a number selected from one through four;
wherein each of p and q is a number selected from zero through
five; wherein X is selected from ##STR4## wherein Z is selected
from ##STR5## wherein R.sup.12 may be selected from hydrido, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,
alkoxyalkyl, hydroxyalkyl, alkanoyl, aralkanoyl, aroyl, aminoalkyl,
monoalkylaminoalkyl and dialkylaminoalkyl; wherein each of R.sup.13
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy,
aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo,
cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl
and alkanoyl; wherein A is selected from aryl, heteroaryl, aryloxy,
heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino,
heteroarylamino, aralkylamino, heteroaralkylamino, arylthio,
heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of
the foregoing A groups can be further substituted with one or more
substituents independently selected from hydrido, hydroxy, alkyl,
cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy,
aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino,
monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl,
alkenyl and alkynyl; or a pharmaceutically acceptable salt
thereof.
A more preferred family of compounds within Formula I consists of
those compounds wherein R.sup.1 is selected from hydrido,
loweralkyl, cycloalkyl of three to about eight carbon atoms,
hydroxyloweralkyl, haloloweralkyl, cycloalkylalkyl of four to about
eight carbon atoms, loweralkoxyloweralkyl, phenylloweralkyl,
phenyl, loweralkenylloweralkyl, loweralkynylloweralkyl and
carboxyloweralkyl; wherein each of R.sup.2 and R.sup.3 is
independently selected from hydrido, loweralkyl, cycloalkyl of
three to about eight carbon atoms, hydroxyloweralkyl,
haloloweralkyl, cycloalkylalkyl of four to about eight carbon
atoms, loweralkoxyloweralkyl, phenylloweralkyl, phenyl,
loweralkenyl, loweralkynyl, loweralkenylloweralkyl,
loweralkynylloweralkyl, carboxyloweralkyl, loweralkanoyl,
loweralkoxycarbonyl, carboxy and cyanoloweralkyl; wherein R.sup.2
and R.sup.3 may be taken together to form a saturated or partially
unsaturated carbocyclic group having three to eight ring carbons;
wherein each of R.sup.4 through R.sup.11 is independently selected
from hydrido, hydroxy, loweralkyl, cycloalkyl of three to about
eight carbon atoms, cycloalkylalkyl of four to about eight carbon
atoms, phenylloweralkyl, phenyl, loweralkoxy, phenoxy,
phenylloweralkoxy, loweralkoxyloweralkyl, haloloweralkyl,
hydroxyloweralkyl, cyano, amino, monoloweralkylamino,
diloweralkylamino, carboxy, carboxyloweralkyl, loweralkanoyl,
loweralkenyl and loweralkynyl; wherein R.sup.4 saturated or
partially unsaturated carbocyclic group having three to eight ring
carbons; wherein each of n and m is a number selected from one
through four; wherein each of p and q is a number selected from
zero through five; wherein X is selected from ##STR6## wherein Z is
selected from ##STR7## wherein R.sup.12 may be selected from
hydrido, loweralkyl, cycloalkyl of three to about eight carbon
atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl,
phenylloweralkyl, heteroaryl, loweralkoxyloweralkyl,
hydroxyloweralkyl, loweralkanoyl, phenylalkanoyl, benzoyl,
aminoloweralkyl, monoloweralkylaminoloweralkyl and
diloweralkylaminoloweralkyl; wherein each of R.sup.13 through
R.sup.16 is independently selected from hydrido, hydroxy,
loweralkyl, cycloalkyl of three to about eight carbon atoms,
cycloalkylalkyl of four to about eight carbon atoms,
phenyloweralkyl, phenyl, loweralkoxy, phenylloweralkoxy, phenoxy,
loweralkoxyloweralkyl, haloloweralkyl, hydroxyloweralkyl, halo,
cyano, amino, monoloweralkylamino, diloweralkylamino, carboxy,
carboxyloweralkyl and loweralkanoyl; wherein A is selected from
phenyl, naphthyl, heteroaryl, phenoxy, naphthyloxy, heteroaryloxy,
phenylloweralkoxy, naphthylloweralkoxy, heteroarylloweralkoxy,
phenylamino, naphthylamino, heteroarylamino, phenylloweralkylamino,
naphthylloweralkylamino, heteroaralkylamino, phenylthio,
naphthylthio, heteroarylthio, phenylloweralkylthio and
heteroarylloweralkylthio; wherein any of the foregoing A groups can
be further substituted with one or more substituents independently
selected from hydrido, hydroxy, loweralkyl, cycloalkyl of three to
about eight carbon atoms, cycloalkylalkyl of four to about eight
carbon atoms, phenylloweralkyl, phenyl, loweralkoxy, phenoxy,
phenyloweralkoxy, loweralkoxyloweralkyl, halo, haloloweralkyl,
hydroxyloweralkyl, cyano, amino, monoloweralkylamino,
diloweralkylamino, carboxy, carboxyloweralkyl, loweralkanoyl,
loweralkenyl and loweralkynyl; or a pharmaceutically acceptable
salt thereof.
A more highly preferred family of compounds of Formula I consists
of those compounds wherein R.sup.1 is selected from hydrido,
loweralkyl, cycloalkyl of three to about eight carbon atoms,
cycloalkylalkyl of four to about eight carbon atoms, benzyl,
phenyl, loweralkenylloweralkyl and loweralkynyllowaralkyl; wherein
each of R.sup.2 and R.sup.3 is independently selected from hydrido,
loweralkyl, cycloalkyl of three to about eight carbon atoms,
cycloalkylalkyl of four to about eight carbon atoms, benzyl,
phenyl, loweralkenyl, loweralkynyl, loweralkenylloweralkyl,
loweralkynylloweralkyl, loweralkanoyl and loweralkoxycarbonyl;
wherein R.sup.2 and R.sup.3 may be taken together to form a
saturated or partially unsaturated carbocyclic group having three
to eight ring carbons; wherein each of R.sup.4 through R.sup.11 is
independently selected from hydrido, hydroxy, loweralkyl,
cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of
four to about eight carbon atoms, benzyl, phenyl, loweralkoxy,
phenoxy, benzyloxy, loweralkoxyloweralkyl, haloloweralkyl,
hydroxyloweralkyl, loweralkanoyl, loweralkenyl and loweralkynyl;
wherein R.sup.4 and R.sup.5 may be taken together to form oxo or to
form a saturated or partially unsaturated carbocyclic group having
three to eight ring carbons; wherein each of n and m is a number
selected from one through four; wherein each of p and q is a number
selected from zero through five; wherein X is selected from
##STR8## wherein Z is selected from ##STR9## wherein R.sup.12 may
be selected from hydrido, loweralkyl, cycloalkyl of three to about
eight carbon atoms, cycloalkylalkyl of four to about eight carbon
atoms, phenyl, benzyl, loweralkoxyloweralkyl and hydroxyloweralkyl;
wherein each of R.sup.13 through R.sup.16 is independently selected
from hydrido, hydroxy, loweralkyl, cycloalkyl of three to about
eight carbon atoms, cycloalkylalkyl of four to about eight carbon
atoms, benzyl, phenyl, loweralkoxy, benzyloxy, phenoxy,
loweralkoxyloweralkyl, haloloweralkyl, hydroxyloweralkyl and halo;
wherein A is selected from phenyl, naphthyl, thienyl, phenoxy,
benzyloxy, naphthyloxy, thiophenoxy, phenylamino, benzylamino,
naphthylamino, phenylthio, benzylthio and naphthylthio; wherein any
of the foregoing A groups can be further substituted with one or
more substituents independently selected from hydrido, hydroxy,
loweralkyl, cycloalkyl of three to about eight carbon atoms,
cycloalkylalkyl of four to about eight carbon atoms, loweralkoxy,
loweralkoxyloweralkyl, halo, haloloweralkyl, hydroxyloweralkyl,
amino, monoloweralkylamino, diloweralkylamino, loweralkanoyl,
loweralkenyl and loweralkynyl; or a pharmaceutically acceptable
salt thereof.
A family of compounds of particular interest within Formula I are
compounds embraced by Formula II: ##STR10## wherein R.sup.1 is
selected from hydrido, loweralkyl, cycloalkylalkyl of four to six
carbon atoms and loweralkenylloweralkyl; wherein each of R.sup.2
and R.sup.3 is independently selected from hydrido and loweralkyl;
wherein each of R.sup.4 through R.sup.7, R.sup.10 and R.sup.11 is
independently selected from hydrido, hydroxy, loweralkyl, benzyl,
phenoxy, benzyloxy and haloloweralkyl; wherein n is a number
selected from four through six; wherein p is a number selected from
zero through four; wherein q is a number selected from three
through five; wherein A is selected from phenyl, naphthyl and
thienyl; wherein any of the foregoing A groups can be further
substituted with one or more substituents independently selected
from hydrido, hydroxy, loweralkyl, loweralkoxy, halo,
haloloweralkyl, amino, monoloweralkylamino and diloweralkylamino;
or a pharmaceutically acceptable salt thereof.
A more preferred family of compounds within Formula II consists of
compounds wherein R.sup.1 is selected from hydrido, methyl, ethyl,
propyl, cyclopropylmethyl, allyl and dimethylallyl; wherein each of
R.sup.2 and R.sup.3 is independently selected from hydrido, methyl,
ethyl and propyl; wherein each of R.sup.4 through R.sup.7, R.sup.10
and R.sup.11 is independently selected from hydrido, hydroxy,
methyl, ethyl, propyl, benzyl, phenoxy, benzyloxy and
haloloweralkyl; wherein n is a number selected from four or five;
wherein p is a number selected from zero through two; wherein q is
a number selected from three or four; wherein A is phenyl or
naphthyl; wherein any of the foregoing A groups can be further
substituted with one or more substituents independently selected
from hydroxy, methyl, ethyl, propyl, methoxy, ethoxy,
methylenedioxy, halo, trifluoromethyl, amino, methylamino and
dimethylamino; or a pharmaceutically acceptable salt thereof.
Of highest interest are the following specific compounds:
(.+-.)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)-cyclohexylami
ne;
1S,
2R-(+)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclohexylami
ne;
1R,
2S-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclohexylami
ne;
(.+-.)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)cyclo
hexylamine;
1S,
2R-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)cycl
ohexylamine;
1R,
2S-(+)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)cycl
ohexylamine;
(.+-.)-cis-N-methyl-N-(2-phenylethyl)-2-(1-pyrrolidinyl)-cyclohexylamine;
(+)-cis-N-methyl-N-[2-(.beta.-naphthyl)ethyl]-2-(1-pyrrolidinyl)-cyclohexyl
amine;
1S,
2R-(-)-cis-N-methyl-N-[2-(3,4-methylenedioxyphenyl)-ethyl]-2-(1-pyrrolidin
yl)cyclohexylamine;
1R,
2S-(+)-cis-N-methyl-N-[2-(3,4-methylenedioxyphenyl)-ethyl]-2-(1-pyrrolidin
yl)cyclohexylamine;
1R,
2S-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-ethyl-2-(1-pyrrolidinyl)cyclo
hexylamine;
1R,
2S-(-)-cis-N-cyclopropylmethyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrol
idinyl)cyclohexylamine; and
1R,
2S-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-(1-propyl)-2-(1-pyrrolidinyl)
cyclohexylamine.
The term "hydrido" denotes a single hydrogen atom (H) which may be
attached, for example, to an oxygen atom to form hydroxyl group.
Where the term "alkyl" is used, either alone or within other terms
such as "haloalkyl" and "hydroxyalkyl", the term "alkyl" embraces
linear or branched radicals having one to about twenty carbon atoms
or, preferably, one to about ten carbon atoms. More preferred alkyl
radicals are "lower alkyl" radicals having one to about five carbon
atoms. The term "cycloalkyl" embraces cyclic radicals having three
to about six carbon atoms, such as cyclopropyl and cyclobutyl. The
term "haloalkyl" embraces radicals wherein any one or more of the
alkyl carbon atoms is substituted with one or more halo groups,
preferable selected from bromo, chloro and fluoro. Specifically
embraced by the term "haloalkyl" are monohaloalkyl, dihaloalkyl and
polyhaloalkyl groups. A monohaloalkyl group, for example, may have
either a bromo, a chloro, or a fluoro atom within the group.
Dihaloalkyl and polyhaloalkyl groups may be substituted with two or
more of the same halo groups, or may have a combination of
different halo groups. A dihaloalkyl group, for example, may have
two bromo atoms, such as a dibromomethyl group, or two chloro
atoms, such as a dichloromethyl group, or one bromo atom and one
chloro atom, such as a bromochloromethyl group. An example of a
polyhaloalkyl is a trifluoromethyl group. The terms "alkylol" and
"hydroxyalkyl" embrace linear or branched alkyl groups having one
to about ten carbon atoms any one of which may be substituted with
one or more hydroxyl groups. The term "alkenyl" embraces linear or
branched radicals having two to about twenty carbon atoms,
preferable two to about ten carbon atoms, and containing at least
one carbon-carbon triple bond. The terms "cycloalkenyl" and
"cycloalkynyl" embrace cyclic radicals having three to about ten
ring carbon atoms including, respectively, one or more double or
triple bonds involving adjacent ring carbons. The terms "alkoxy"
and "alkoxyalkyl" embrace linear or branched oxy-containing
radicals each having alkyl portions of one to about ten carbon
atoms, such as methoxy group. The "alkoxy" or "alkoxyalkyl"
radicals may be further substituted with one or more halo atoms,
such as fluoro, chloro or bromo, to provide haloalkoxy or
haloalkoxyalkyl groups. The term "heteroaryl" embraces aromatic
ring systems containing one or two hetero atoms selected from
oxygen, nitrogen and sulfur in a ring system having five or six
ring members, examples of which are thienyl, furanyl, pyridinyl,
thiazolyl, pyrimidyl and isoxazolyl. The term "alkylene chain"
describes a chain of two to six methylene (--CH.sub.2 --) groups
which may form a cyclic structure with or without a hetero atom in
the cyclic structure.
Specific examples of alkyl groups are methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, iso-butyl, tertbutyl, n-pentyl,
iso-pentyl, methyl-butyl, dimethylbutyl and neopentyl. Typical
alkenyl and alkynyl groups may have one unsaturated bond, such as
an allyl group, or may have a plurality of unsaturated bonds, with
such plurality of bonds either adjacent, such as allene-type
structures, or in conjugation, or separated by several saturated
carbons.
Included within the family of compounds of Formulas I-II are the
tautomeric forms of the described compounds, isomeric forms
including diastereoisomers, and the pharmaceutically-acceptable
salts thereof. The term "pharmaceutically-acceptable salts"
embraces salts commonly used to form alkali metal salts and to form
addition salts of free acids or free bases. Since the compounds of
Formulas I-II contain basic nitrogen atoms, such salts are
typically acid addition salts. The phrase
"pharmaceutically-acceptable salts" is not intended to embrace
quaternary ammonium salts. The nature of the salt is not critical,
provided that it is pharmaceutically acceptable, and acids which
may be employed to form salts are, of course, well known to those
skilled in this art. Examples of acids which may be employed to
form pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, sulfuric acid and phosphoric
acid, and such organic acids as maleic acid, succinic acid and
citric acid. Other pharmaceutically acceptable salts include salts
with alkali metals or alkaline earth metals, such as sodium,
potassium, calcium and magnesium, or with organic bases, such as
dicyclohexylamine. All of these salts may be prepared by
conventional means by reacting, for example, the appropriate acid
or base with the corresponding compound of Formulas I-II
General Synthetic Procedures
Compounds of Formulas I and II may be prepared in accordance with
the following generic procedures, within which specific schemes are
shown for Formula II type compounds. ##STR11## wherein R.sup.1,
R.sup.10, R.sup.11, and q are as defined previously; and wherein B
represents a protecting group such as acetyl, benzoyl,
t-butyloxy-carbonyl or benzyloxycarbonyl.
A process for preparing the compounds of the invention starts with
protected hydroxyamines of general structure 1 where R.sup.1,
R.sup.10, R.sup.11, and q have the value assigned previously; and
where B represents a protecting group such as acetyl, benzoyl or
t.-butyloxycarbonyl. The alcohol is oxidized to the ketone 2
employing oxidizing agents such as pyridinium chlorochromate,
chromium trioxide, potassium dichromate, or other oxidizing agents
familiar to those skilled in the art. This oxidation can be
achieved in either aqueous or organic solvents, depending on the
oxidizing agent of choice, and at temperatures ranging from
-60.degree. to reflux of the reaction mixture. ##STR12## wherein B,
R.sup.1, R.sup.6, R.sup.7, R.sup.10, R.sup.11, n, and q are as
defined previously.
In the second step of the process, ketones of general structure 2
are converted to enamines of general structure 4 by mixing 2 with
amines of general structure 3 where B, R.sup.1, R.sup.6, R.sup.7,
R.sup.10, R.sup.11, n, and q are as defined previously. The
compounds can be combined neat or in a variety of solvents such as
toluene, xylene, or chloroform and with an acid such as
p-toluenesulfonic acid, acetic acid, or trifluoroacetic acid. The
temperature of the reaction can vary from room temperature to
reflux of the reaction mixture. ##STR13## wherein B, R.sup.1,
R.sup.6, R.sup.7, R.sup.10, R.sup.11, n, and q are as defined
previously.
In the third step of the process, enamines of general structure 4
are reduced to amines of general structure 5 by employing reducing
agents such as lithium aluminum hydride, sodium borohydride, sodium
cyanoborohydride, catalytic hydrogenation, or other reducing agents
familiar to those skilled in the art. This reduction can be
accomplished in either protic or aprotic solvents, depending on the
reducing agent of choice, and at temperatures ranging from room
temperature to reflux of the reaction mixture. ##STR14## wherein B,
R.sup.1, R.sup.6, R.sup.7, R.sup.10, R.sup.11, n, and q are as
defined previously.
In the fourth step of the process, amines of general structure 5
are converted to amines of general structure 6 by removal of the
blocking group B. The conversion is best achieved by mixing 5 with
a base such as sodium hydroxide, potassium hydroxide or other bases
familiar to those skilled in the art. The reagents are combined in
a protic solvent such as water, ethylene glycol, or methanol. The
temperature of the reaction can vary from room temperature to
reflux of the reaction mixture.
Step 4(b)
Alternately, amines of general structure 6 can be prepared from
amines of general structure 5 by removal of the blocking group B by
mixing 5 with an acid such as hydrochloric acid, sulfuric acid,
trifluoroacetic acid or other acids familiar to those skilled in
the art. The reagents are combined in a protic solvent such as
water, ethylene glycol, or methanol. The temperature of the
reaction can vary from room temperature to reflux of the reaction
mixture. ##STR15## wherein A, R.sup.1, R.sup.4 through R.sup.7,
R.sup.10, R.sup.11, n, p, and q are as defined previously; and
wherein L.sup.1 is a good leaving group such as chloro, bromo,
acyloxy, or hydroxy.
In the fifth step of the process, amines of general structure 6 are
converted to amides of general structure 8 where A, R.sup.4, and
R.sup.5 have the value assigned previously and L.sup.1 is a good
leaving group such as chloro, bromo, acyloxy, or hydroxy. The
conversion can be best achieved by mixing the reagents neat or in
an aprotic solvent such as tetrahydrofuran, methylene chloride, or
ether. The reaction can be run in the absence or presence of an
activating agent such as dicyclohexylcarbodiimide or phosphorus
oxychloride, depending on the leaving group of choice. The
temperature of the reaction can vary from 0.degree. to reflux of
the reaction mixture. ##STR16## wherein A, R.sup.1, R.sup.4 through
R.sup.7, R.sup.10, R.sup.11, n, p, and q are as defined
previously.
In the sixth step of the process, amides of general structure 8 are
converted to amines of general structure 9 by employing reducing
agents such as lithium aluminum hydride, sodium borohydride, sodium
cyanoborohydride, or other reducing agents familiar to those
skilled in the art. This reduction can be accomplished in either
protic or aprotic solvents, depending on the reducing agent of
choice, and at temperatures ranging from room temperature to reflux
of the reaction mixture.
Step 5(b)
Alternately, amines of general structure 11 can be prepared
according to the following generic procedure. ##STR17## wherein A,
R.sup.1 through R.sup.7, R.sup.10, R.sup.11, n, p, and q are as
defined previously; and wherein L.sup.2 is a good leaving group
such as halogen, tosylate, mesylate, brosylate or OH.
Amines of general structure 11 can be alternately prepared by
combining amines of general structure 6 with compounds of general
structure 10 where A, R.sup.1 through R.sup.7, R.sup.10, R.sup.11,
n, p, and q have the values assigned previously and where L.sup.2
is a good leaving group such as halogen, tosylate, mesylate,
brosylate or OH. The compounds can be combined in a variety of
solvents such as toluene, xylenes, dimethylformamide,
hexamethylphosphoramide, or ethanol. The temperature of the
reaction can vary from room temperature to reflux of the reaction
mixture.
The following Examples I.congruent.XI are detailed descriptions of
the methods of preparation of compounds of Formula I. These
detailed preparations fall within the scope of, and serve to
exemplify, the above described Generic Procedures which form part
of the invention. These Examples I-XI are presented for
illustrative purposes only and are not intended as a restriction on
the scope of the invention. All parts are by weight unless
otherwise indicated. Most of the commercially available starting
materials were obtained from Aldrich Chemical Company, Milwaukee,
Wis.
EXAMPLE I
(.+-.)-trans-2-Benzamidocyclohexanol
(.+-.)-trans-2-Aminocyclohexanol (241 gm) was combined with
chloroform (2000 ml), water (2000 ml) and sodium bicarbonate (352
gm) and stirred. Benzoyl chloride (352 gm) was added dropwise to
the stirred solution and stirring was continued for 1 hr. The
product was filtered and washed with water. The white solid was
dried at 80.degree. C. to provide the product (mp
172.degree.-173.degree. C.).
EXAMPLE II
(.+-.)-2-Benzamidocyclohexanone
A solution of Jones reagent (1135 ml) was prepared by combining
CrO.sub.3 (140 gm) and H.sub.2 SO.sub.4 (122 ml) with water. The
Jones reagent was added dropwise to a cooled, stirred mixture of
(.+-.)-trans-2-benzamidocyclohexanol (260 gm) and acetone (3000 ml)
and the stirring continued 1 hr. A 20% solution of K.sub.2 CO.sub.3
in water was added to the reaction solution until the evolution of
carbon dioxide subsided. The resulting layers were separated and
the bottom layer extracted with ethyl acetate. The ethyl acetate
was combined with the material from the upper layer and the
resulting solution washed with water and saturated sodium chloride
solution. The organic solution was concentrated on a rotary
evaporator and the residue was recrystallized from aqueous
2-propanol to provide the product (mp 126.degree.-127.degree.
C.).
EXAMPLE III
(.+-.)-cis-2-(1-Pyrrolidinyl)-N-benzoylcyclohexylamine
hydrochloride
(.+-.)-2-Benzamidocyclohexanone (213 gm) was combined with
pyrrolidine (103 ml), p-toluenesulfonic acid (9.3 gm) and benzene
(3300 ml) and heated to reflux for 23 hours. Additional pyrrolidine
(103 ml) was added to the reaction mixture and the heating
continued for 24 hours. The solvent was removed on a rotary
evaporator to provide a crude enamine mixture. The crude material
was dissolved in ethyl acetate (100 gm/200 ml) and hydrogenated
over 10% Pd on carbon at 50 psi for 1.5 hours. The mixture was
filtered through celite and the filtrate was concentrated on a
rotary evaporator. The residue was combined with citric acid
monohydrate (306 gm), water (1300 ml) and methylene chloride (500
ml) and shaken until all solid material had dissolved. The layers
were separated and the aqueous layer was washed with additional
methylene chloride. Excess concentrated aqueous ammonia was added
to the aqueous solution and the mixture extracted with methylene
chloride. The combined organic extracts were dried (Na.sub.2
SO.sub.4) and the solvent removed on a rotary evaporator. The crude
material was dissolved in methanol (200 ml) and treated with an
excess of a solution of anhydrous hydrogen chloride in methanol.
The solution was adjusted to a final volume of 700 ml by the
addition of 2-propanol and the methanol was removed by distillation
while maintaining a constant volume of 700 ml by the slow addition
of 2-propanol. The crude product crystallized upon slow cooling and
was filtered. The material was recrystallized from 2-propanol to
provide the product (mp 276.degree.-277.degree. C.).
EXAMPLE IV
(.+-.)-cis-2-(1-Pyrrolidinyl)cyclohexylamine
(.+-.)-cis-2-(1-Pyrrolidinyl)-N-benzoylcyclohexylamine
hydrochloride (10 gm) was combined with ethylene glycol (50 ml) and
potassium hydroxide (10 gm) and the solution was heated to reflux
for 48 hours. The solution was diluted with water (200 ml) and
extracted with ether. The ether was removed on a rotary evaporator
and the residue was distilled (94.degree. C. at 0.05 mm Hg) to
provide the product.
EXAMPLE V
(-)-cis-2-(1-Pyrrolidinyl)cyclohexylamine
(.+-.)-cis-2-(1-pyrrolidinyl)cyclohexylamine (10 gm ) was combined
with ethanol (10 ml) and 2-propanol (40 ml) and warmed to
60.degree. C. A solution of R-(-)-mandelic acid (18 gm) in ethanol
(50 ml) and 2-propanol (200 ml) was warmed to 60.degree. C. and
added to the amine solution. The solution was allowed to cool
slowly to room temperature and the resulting crystals were
filtered. The crystals were washed with 20% ethanol in 2-propanol,
followed by ether and dried under vacuum. The crystals were
recrystallized from 20% ethanol in 2-propanol to provide the
mandelate salt. The salt was partitioned between 30% NaOH and
chloroform and the layers separated. The chloroform was removed on
a rotary evaporator to provide the product as a colorless oil which
solidified upon standing (bp 86.degree. C., at 0.1 mm Hg,
[.alpha.].sub.D (MeOH)=-2.95.degree.).
EXAMPLE VI
(+)-cis-2-(1-Pyrrolidinyl)cyclohexylamine
The mother liquors from Example V were concentrated on a rotary
evaporator. The residue was partitioned between 30% NaOH and
chloroform and the layers separated. The chloroform was removed on
a rotary evaporator and the residue was distilled under high
vacuum. The distillate was combined with ethanol (10 ml) and
2-propanol (40 ml)and warmed to 60.degree. C. A solution of
R-(-)-mandelic acid (18 gm) in ethanol (50 ml) and 2-propanol (200
ml) was warmed to 60.degree. C. and added to the amine solution.
The solution was allowed to cool slowly to room temperature and the
resulting crystals were filtered. The crystals were washed with 20%
ethanol in 2-propanol, followed by ether and dried under vacuum.
The crystals were recrystallized from 20% ethanol in 2-propanol to
provide the mandelate salt. The salt was partitioned between 30%
NaOH and chloroform and the layers separated. The chloroform was
removed on a rotary evaporator to provide the product as a
colorless oil which solidified upon standing (bp 86.degree. C. at
0.1 mm Hg, [.alpha.].sub.D (MeOH)=-+2.21.sqroot.).
EXAMPLE VII
1R,2S-(-)-cis-2-(1-Pyrrolidinyl)-N-methylcyclohexylamine
(-)-cis-2-(1-pyrrolidinyl)cyclohexylamine (2 gm) was combined with
ethyl formate (20 ml) and heated to reflux 10 minutes. The solvent
was removed on a rotary evaporator. The residue was combined with
anhydrous tetrahydrofuran (10 ml) and treated with 1 M lithium
aluminum hydride in tetrahydrofuran (16 ml). The mixture was heated
to reflux 1 hour and cooled in an ice bath. The mixture was treated
with water (2.4 ml) and 15% NaOH (0.6 ml), filtered, and the
solvent removed on a rotary evaporator. The residue was distilled
under high vacuum to provide the product as a colorless oil (bp
76.degree. C. at 1.1 mm Hg, [.alpha.].sub.D
(MeOH)=-31.7.degree.).
EXAMPLE VIII
(.+-.)-2-(N-t-Butyloxycarbonyl-N-methylamino)cyclohexanone
(.+-.)-trans-N-methyl-2-aminocyclohexanol (142 gm) was combined
with t-butyldicarbonate (240 gm), potassium bicarbonate (458 gm),
and water (1000 ml) and stirred overnight. The aqueous mixture was
extracted with methylene chloride and the organic extract was dried
(Na.sub.2 SO.sub.4) and concentrated on a rotary evaporator. The
residue was recrystallized from isooctane to provide a white solid
(mp 82.degree.-83.degree. C.). The solid was dissolved in methylene
chloride (500 ml) and added dropwise to a stirred solution of
pyridinium chlorochromate (334 gm) in methylene chloride (1000 ml).
After the addition, stirring was continued for 3 hours. The mixture
was diluted with ether (1500 ml) and filtered through florisil. The
solvent was removed on a rotary evaporator and the residue was
distilled (115.degree. C. at 0.9 mm Hg) to provide a colorless
oil.
EXAMPLE IX
(.+-.)-cis-2-[1-Pyrrolidinyl]-N-methylcyclohexylamine
(.+-.)-cis-2-Pyrrolidinyl-N-t-butyloxycarbonyl-N-methylcyclohexylamine
(247 gm) was slowly added to 6 M hydrochloric acid at 60.degree. C.
with vigorous stirring. The solution was stirred an additional 5
minutes at 60.degree. C. and poured onto ice (200 gm). Excess
concentrated aqueous ammonia was added and the mixture was
extracted with methylene chloride. The combined extracts were dried
(Na.sub.2 SO.sub.4) and the solvent removed on a rotary evaporator.
The residue was distilled (78.degree. C. at 0.3 mm Hg) to give the
product as a colorless oil.
EXAMPLE X
(.+-.)-cis-N-[2-(3,4-Dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)cyclo
hexylamine (Compound No. 1).
(.+-.)-cis-2-Pyrrolidinyl-N-methylcyclohexylamine (3 gm) was
combined with anhydrous dimethylformamide (70 ml) and warmed to
60.degree. C. 2-(3,4-dichlorophenyl)ethyl methanesulfonate (14 gm)
was added to the warm amine solution over 3 days. The reaction
mixture was diluted to 500 ml with water and extracted with
chloroform. The combined extracts were washed with water and
treated with a solution of hydrogen bromide in methanol. The
solution was concentrated on a rotary evaporator and the residual
dimethylformamide removed by distillation under high vacuum. The
residue was triturated with 2-propanol to provide a white solid.
The solid was recrystallized from 2-propanol. Analytical data are
reported in Table I.
EXAMPLE IX
(.+-.)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidnyl)-cyclohexylamin
e (Compound No. 8)
(.+-.)-cis-2-(1-pyrrolidinyl)cyclohexylamine (5 gm) was combined
with pyridine (1.2 gm), chloroform (200 ml),
3,4-dichlorophenylacetic acid (9.15 gm), and
dicyclohexylcarbodiimide (12.3 gm) and the mixture was stirred for
12 hr at room temperature. The mixture was filtered, the
precipitate was washed with ether (100 ml) and the filtrate and
ether wash were combined. The organic solution was diluted with
ether (200 ml) and extracted with 10% citric acid in water (300
ml). The acid layer was washed with ether (2.times.200 ml), then
treated with excess concentrated aqueous ammonia until basic. The
resulting mixture was extracted with methylene chloride
(2.times.200 ml) and the combined organic extracts were washed with
water (2.times.50 ml) and concentrated on a rotary evaporator. The
resulting white solid was combined with tetrahydrofuran (25 ml) and
added dropwise to a solution of AlH.sub.3 in tetrahydrofuran (76.2
ml of a 0.665 M solution) at room temperature. After the addition,
the mixture was poured into 15 % NaOH and the resulting mixture was
extracted with ether (3.times.100 ml). The ether was removed on a
rotary evaporator and the residue was dissolved in ethanol (100
ml). The ethanol was removed on a rotary evaporator and the residue
was converted to the hydrogen bromide salt which was recrystallized
from ethanol. Analytical data are reported in Table I.
Table I is a list of 13 specific compounds of most interest within
Formula I. The preparation of representative compounds from Table I
is described in detail in Example Procedures I-XI, above. The
remaining compounds may likewise be prepared in accordance with the
above-described Example Procedures.
TABLE I Compound Elemental Analysis Melting Specific Mass Spectral
No. Name Structure Theor. Found Point Rotation [.alpha.].sub.D
Analysis 1
(+)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrol
idinyl)cyclo-hexylamine.oxalate ##STR18## CHN 56.63 6.79 6.29 56.43
6.916.33 120-125.degree. C. -- -- 2
S,2R-(-)-cis-N-[2-(3,4-dichlorophenyl)-ethyl]-N-methyl-2-(1-pyrrolidin
yl)cyclo-hexylamine.2HBr ##STR19## CHN 44.12 5.85 5.42 44.07 5.88
5.44 215-217.degree. C. -8.6.degree. C.(0.84, MeOH) 3
1R,2S-(+)-cis-N-[2-(3,4-dichlorophenyl)-ethyl[-N-methyl-2-(1-pyrrolidi
nyl)cyclo-hexylamine.2HBr ##STR20## CHN 44.12 5.85 5.42 44.21 5.91
5.40 217-218.degree. C. +8.0.degree. C(0.57, MeOH) 4
(.+-.)-cis-N-methyl-N-(2-phenylethyl)-2-(1-pyrro-lidinyl)cyclohexylami
ne ##STR21## -- -- oil M.sup.+ (found) 286.242Requires 286.241 5
(.+-.)-cis-N-methyl-N-[2-(2-naphthyl)ethyl]-2-(1-pyrrolidinyl)cyclo-he
xylamine ##STR22## -- -- oil M.sup.+ (found) 336.256Requires
335.257 6
1S,2R-(-)-cis-N-methyl-N-[2-(3,4-methylenedioxy-phenyl)ethyl]-2-(1-pyr
rolidinyl)cyclo-hexylamine.2HBr ##STR23## CHN 48.79 6.55 5.69 48.68
6.59 5.68 248-249.degree. C. -13.0.degree. C.(3.99, H.sub.2 O) -- 7
1R,2S-(+)-cis-N-methyl-N-[2-(3,4-methylenedioxy-phenyl)ethyl]-2-(1-pyr
rolidinyl)cyclo-hexylamine.2HBr ##STR24## CHN 48.79 6.55 5.69 48.64
6.60 5.62 248-249.degree. C. + 15.2.degree. ( C.2.16, H.sub.2 O) --
8
(.+-.)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)-cyclohex
ylamine.2HBr ##STR25## CHN 42.96 5.57 5.57 43.04 5.65 5.54
274-275.degree. C. -- -- 9
1S,2R-(+)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclo-hex
ylamine.2HBr ##STR26## CHN 42.96 5.57 5.57 43.03 5.62 5.59
280.5-281.5.degree. C. +11.5.degree. C.(0.57, MeOH) 10
1R,2S-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclo
-hexylamine.2HBr ##STR27## CHN 42.96 5.57 5.57 43.03 5.615.57
280-281.degree. C. -11.1.degree. C.(0.32, MeOH) -- 11
1R,2S-(-)-cis-N-[2-(3,4-dichbrophenyl)ethyl]-N-ethyl-2-(1-pyrrolidiny
l)cyclohexylamine.2HI ##STR28## CHN 38.40 5.12 4.48 38.47 5.22 4.51
225.5-226.degree. C. -2.1.degree. C(0.42, MeOH) 12
1R,2S-1-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-cyclopropyl-methyl-2-
(1-pyrrol-idinyl)cyclohexylamine.2fumarate ##STR29## CHN 57.42 6.38
4.47 57.41 6.57 4.72 152-154.degree. C. -23.8.degree. ( C..039,
MeOH) 13
1R,2S-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-(1-propyl)-2-(1-p
yrrolidinyl)cyclohexylamine.fumarate.H.sub.2 O ##STR30## CHN 58.03
7.35 5.41 58.03 7.06 5.66 169.5-170.degree. C. -11.1.degree.
C.0.38, MeOH)
Biological Evaluation
Radioreceptor Assay
Compounds #1-3 were compared against di-o-tolylguanidine (DTG) [E.
Weber et al, Proc. Nat'l. Acad. Sci., 8784-8788, 1986] to determine
the relative potency of the compounds interacting with the sigma
receptor. To determine the effects of the compounds in a sigma
receptor assay, crude membrane preparations were prepared as
follows. Brains from male Sprague-Dawley rats were homogenized in
10 volumes (wt/vol) of 0.32 M sucrose, using a Polytron grinder.
The homogenate was centrifuged at 900.times.G for 10 minutes at
4.degree. C. The supernatant was collected and centrifuged at
22,000.times.g for 20 minutes at 4.degree. C. The pellet was
resuspended in 10 volumes of 50 mM Tris/HCl buffer (pH 7.4) and
centrifuged at 22,000.times.g for 20 minutes at 4.degree. C. The
pellet was resuspended in 5 mM Tris/HCl buffer (pH 7.4) to give a
final concentration of 250 mg/ml of the crude material. Incubation
tubes were prepared in triplicate and contained 0.1 ml of tissue
suspension, 2 nM of [.sup.3 H]-(+)-1-propyl-3-(3-hydroxyphenyl)
piperidine {[.sup.3 H]-3-(+)-PPP}, and varying concentrations of
the displacing ligand (0.1-1000 nM) in a final volume of 0.5 ml.
After a 1 hr incubation at room temperature, the contents of the
test tubes were filtered through GS filter paper which had been
presoaked for at least 2 hours in 0.05% polyethyleneamine. The test
tubes were rinsed three times with Tris/HCl buffer. Radioactivity
on the filters was determined and IC.sub.50 values were calculated
from inhibition curves using the method of Cheng and Prusoff
[Biochem. Pharmacol., 22, 3099-3108, 1973].
TABLE II ______________________________________ Ki apparent (nM)
Test Compound (units + SEM) ______________________________________
DTG 47 .+-. 5 Compound No. 1 230 .+-. 70 Compound No. 2 30 .+-. 10
Compound No. 3 20 .+-. 1 ______________________________________
BLOCKAGE OF APOMORPHINE-INDUCED CLIMBING
Compounds of the invention were evaluated for their ability to
block apomorphine-induced climbing. The evaluation of the compounds
followed the method outlined by Protais [Psychopharmacol., 50, 1-6,
1976]. Swiss-Webster mice, weighing 20-25 g, are pretreated with
the compounds of the invention by i.p. or s.c. adiminstration at
various times before 2 mg/kg apomorphine is administered s.c. in a
volume of 1 ml/kg. All test compounds are administered in a volume
of 10 ml/kg. Mice are rated at 10 and 20 minutes after apomorphine
administration using the following rating scale: (0) forepaws on
the floor, (1) forefeet holding the bars, and (2) four paws holding
bars. Dose-response curves are analyzed by a computerized Finney
assay [Statistical Methods in Biological Assays, 2nd Edn., Hatner
Pub. Co., New York (1964)]. Compound No. 3 completely blocked
apomorphine-induced climbing at a dose of 10 mg/kg.
Forebrain Ischemia Assay
Male Mongolian gerbils, 50-70 gm, were used as subjects. Compound
No. 3 (50 mg/kg) was injected i.p. 30 minutes prior to carotid
occlusion into 6 gerbils. In preparation for surgical procedures,
the animals were lightly anesthetized with halothane and placed
upside down on a heated pad with their snout within a nosecone.
Nitrous oxide (70%): oxygen (30%) plus 0.5% halothane was
circulated through the nosecone to provide continuous anesthesia
throughout the surgical procedure. A midline incision was made in
the neck and the carotid arteries were exposed. A length of suture
thread was placed under each carotid. The thread was then tightened
around each carotid and pressure applied to the thread to insure
flow as occluded. Flow was occluded for 15 minutes and then the
thread was removed. The carotids were visually inspected to confirm
that reflow had occurred. The wound was then closed with autoclips
and the gerbils allowed to recover. Following surgery, the gerbils
were kept alive for 7 days. They were anesthetized with 100 mg/kg
sodium pentobarbital and perfused transcardially with saline (with
heparin) followed by buffered formalin. The brain was removed,
trimmed and prepared for histological processing. Sections (10
microns) were stained with thionin. At 7 days following the
ischemic insult, damaged neurons have been cleared away by glia and
the extent of damage can be ascertained within the vulnerable CA1
region of the hippocampus. The degree of lesion in the CA1 region
of the hippocampus was quantified by counting the pyramidal cell
bodies in a 0.5 mm length of CA1 on the section corresponding to P
1.7 mm in the atlas of Loskota, Lomax and Verity [W. J. Loskota et
al, A Stereotaxic Atlas of the Mongolian Gerbil Brain, Ann Arbor
Science Publishers, Ann Arber, p. 77 (1974)]. The cell loss was
significantly reduced in the gerbils given Compound No. 3
(p<0.01).
Also embraced within this invention is a class of pharmaceutical
compositions comprising one or more compounds of Formula I in
association with one or more non-toxic, pharmaceutically-acceptable
carriers and/or diluents and/or adjuvants (collectively referred to
herein as "carrier" materials) and, if desired, other active
ingredients. The compounds of the present invention may be
administered by any suitable route, preferably in the form a
pharmaceutical composition adapted to such a route, and in a dose
effective for the treatment intended. Therapeutically effective
doses of the compounds of the present invention required to prevent
or arrest the progress of the medical condition are readily
ascertained by one of ordinary skill in the art. The compounds and
composition may, for example, be administered intravascularly,
intraperitoneally, subcutaneously, intramuscularly or
topically.
For oral administration, the pharmaceutical compositions may be in
the form of, for example, a tablet, capsule, suspension or liquid.
The pharmaceutical composition is preferably made in the form of a
dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or capsules.
These may with advantage contain an amount of active ingredient
from about 1 to 250 mg, preferably from about 25 to 150 mg. A
suitable daily dose for a mammal may very widely depending on the
condition of the patient and other factors. However, a dose of from
about 0.1 to 3000 mg/kg body weight, particularly from about 1 to
100 mg/kg body weight, may be appropriate.
The active ingredient may also be administered by injection as a
composition wherein, for example, saline, dextrose or water may be
used as a suitable carrier. A suitable daily dose is from about 0.1
to 100 mg/kg body weight injected per day in multiple doses
depending on the disease being treated. A preferred daily dose
would be from about 1 to 30 mg/kg body weight. Compounds indicated
for prophylactic therapy will preferably be administered in a daily
dose generally in a range from about 0.1 mg to about 100 mg per
kilogram of body weight per day. A more preferred dosage will be a
range from about 1 mg to about 100 mg per kilogram of body weight.
Most preferred is a dosage in a range from about 1 to about 50 mg
per kilogram of body weight per day. A suitable dose can be
administered, in multiple sub-doses per day. These sub-doses may be
administered in unit dosage forms. Typically, a dose or sub-dose
may contain from about 1 mg to about 100 mg of active compound per
unit dosage form. A more preferred dosage will contain from about 2
mg to about 50 mg of active compound per unit dosage form. Most
preferred is a dosage form containing from about 3 mg to about 25
mg of active compound per unit dose.
The dosage regimen for treating a disease condition with the
compounds and/or compositions of this invention is selected in
accordance with a variety of factors, including the type, age,
weight, sex and medical condition of the patient, the severity of
the disease, the route of administration, and the particular
compound employed, and thus may vary widely.
For therapeutic purposes, the compounds of this invention are
ordinarily combined with one or more adjuvants appropriate to the
indicated route of administration. If administered per os, the
compounds may be admixed with lactose, sucrose, starch powder,
cellulose esters of alkanoic acids, cellulose alkyl esters, talc,
stearic acid, magnesium stearate, magnesium oxide, sodium and
calcium salts of phosphoric and sulfuric acids, gelatin, acacia
gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl
alcohol, and then tableted or encapsulated for convenient
administration. Such capsules or tablets may contain a
controlled-release formulation as may be provided in a dispersion
of active compound in hydroxypropylmethyl cellulose. Formulations
for parenteral administration may be in the form of aqueous or
non-aqueous isotonic sterile injection solutions or suspensions.
These solutions and suspensions may be prepared from sterile
powders or granules having one or more of the carriers or diluents
mentioned for use in the formulations for oral administration. The
compounds may be dissolved in water, polyethylene glycol, propylene
glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,
benzyl alcohol, sodium chloride, and/or various buffers. Other
adjuvants and modes of administration are well and widely known in
the pharmaceutical art.
Although this invention has been described with respect to specific
embodiments, the details of these embodiments are not to be
construed as limitations. Various equivalents, changes and
modifications may be made without departing from the spirit and
scope of this invention, and it is understood that such equivalent
embodiments are part of this invention.
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